Paraoxonase 1: evolution of the enzyme and of its role in protecting against atherosclerosis.

Abstract

To review the discoveries which led to the concept that serum paraoxonase 1 (PON1) is inversely related to atherosclerotic cardiovascular disease (ASCVD) incidence, how this association came to be regarded as causal and how such a role might have evolved. Animal models suggest a causal link between PON1 present on HDL and atherosclerosis. Serum PON1 activity predicts ASCVD with a similar reliability to HDL cholesterol, but at the extremes of high and low HDL cholesterol, there is discordance with PON1 being potentially more accurate. The paraoxonase gene family has its origins in the earliest life forms. Its greatest hydrolytic activity is towards lactones and organophosphates, both of which can be generated in the natural environment. It is active towards a wide range of substrates and thus its conservation may have resulted from improved survival of species facing a variety of evolutionary challenges. Protection against ASCVD is likely to be the consequence of some promiscuous activity of PON1, but nonetheless has the potential for exploitation to improve risk prediction and prevention of ASCVD.